Colorectal cancer (CRC) is preventable if detected early. CRC screening saves an estimated 30,000 U.S. lives/year. Current screening recommendations are based on history of CRC, age, family history, and genetics (identifiable mutations in high-penetrance syndromes such as HNPCC). Unfortunately, after taking into account identifiable mutations in all known genetic CRC susceptibility syndromes, >90% of population-based CRC susceptibility remains unexplained. Here, we propose a pilot study to identify genetic variants relevant to population based CRC. Discovery of CRC susceptibility variants will help identify high-risk patients. High-risk patients and their family members can benefit from early detection through frequent colonoscopy, risk modification, chemoprevention, and participation in CRC screening and treatment clinical trials. Because identifiable MLH1, MSH2 and MSH6 mutations in HNPCC underlie 2-5% of CRC patients, we hypothesize that more common susceptibility variants exist in these genes relevant to non-HNPCC population based CRC. Here, we propose a pilot study to identify common MLH1, MSH2 and MSH6 variants that confer CRC susceptibility in American CRC patients through the following aims: SPECIFIC AIM 1: To discover common American MLH1, MSH2 and MSH6 coding and splice-junction variants in 100 CRC patients with increased susceptibility risk factors. We will sequence MLH1, MSH2 and MSH6 coding and peri-exonic sequences from 100 California CRC patients with increased susceptibility risk factors to identify variant alleles. We estimate identifying approximately 75 unique variants. SPECIFIC AIM 2: To test association of MLH1, MSH2 and MSH6 variants with CRC risk. We have previously recruited population-based CRC cases and 1600 controls from Southern California. We will test associations with CRC risk in 500 CRC patients and 500 matched control subjects for the approximately 15 variants most likely to disrupt protein function. We will incorporate into our analyses regression variables for genetic (such as family history of cancer) as well as environmental (such as calcium, folate and non-steroidal anti-inflammatory agent intake) factors.